Maternal age, paternal age, and human chromosome abnormality: nature, magnitude, etiology, and mechanisms of effects.
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Adolescent↗
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Inverse relationship between age at onset of Huntington disease and paternal age suggests involvement of genetic imprinting.
It is well recognized that age at onset of Huntington disease (HD) is strongly influenced by the sex of the affected parent, and this has lead to suggestions that genetic imprinting or maternal specific factors may play a role in the expression of the disease. This study evaluated maternal and paternal ages, birth order, parental age at onset, and sex of the affected parent and grandparent in 1,764 patients in the National HD Roster by using linear-regression techniques which incorporated a weighted least-squares approach to accommodate the correlation among siblings. It was found that paternal age is negatively associated with age at onset of HD, particularly among subjects who inherit the mutant gene from grandfathers. Apparent associations between age at onset and birth order and between age at onset and maternal age were not significant after adjustment for paternal age. The paternal age effect is strongest among juvenile-onset cases and individuals with anticipation of greater than or equal to 10 years, although it is detectable across the entire age-at-onset distribution. The tendency for older fathers, including those not transmitting the HD gene, to have affected offspring with early-onset disease may be consistent with a gene imprinting mechanism involving DNA methylation. Because paternal age in unaffected fathers is also a significant determinant of age at onset, methylation in this context might involve HD modifier genes or the normal HD allele.
Adolescent↗
Increased parental ages and uniparental disomy 15: a paternal age effect?
Parental ages associated with both maternal and paternal uniparental disomy (UPD) of chromosome 15 are highly elevated in comparison to Zurich population-based controls, with mean maternal and paternal ages of 35.6 and 38.1, respectively for UPD patients (diagnosed in Zurich) and 28.0 and 31.0, in controls. The parental ages are also significantly higher than observed for trisomies of other chromosomes diagnosed in Zurich. The higher age of UPD cases may be due to the fact that two errors, both a gain and a loss of a chromosome 15, are necessary. We suggest that gamete complementation, zygote formation from two gametes one of which is nullisomic and the other disomic for the same chromosome, may be a major mechanism of UPD formation, as well as secondary loss of a chromosome in a trisomic conception, and that there is an association between increased paternal age and nondisjunction.
Adult↗
The appropriate upper age limit for semen donors: a review of the genetic effects of paternal age.
There is little evidence to support a correlation between increased paternal age and the incidence of chromosome anomalies. Though a few early studies demonstrated an increased risk of Down syndrome with advanced paternal age, especially after the age of 55, numerous later studies failed to confirm any paternal age effect. Among structural chromosome anomalies, only the inherited reciprocal translocations were found to be more common among children of older fathers. Chromosome analysis of semen donors would rule out this problem. There is evidence, however, that the incidence of serious nonchromosomal birth defects, especially those arising from new autosomal mutations, increases with paternal age. Risk estimates have been established for increased paternal age and contribution to new dominant mutations. The established association between increased paternal age and new autosomal mutations and the fact that most of the disorders associated with such mutations cannot be prenatally diagnosed may be important in establishing the upper age limit for semen donors. Recommendations from the literature are interpreted to advise men to have their children before age 40. This suggestion would obviously benefit immediate offspring and perhaps successive generations as well. The limit of 35 years set by AATB standards, therefore, is in harmony with such benefit, but may be too stringent in eliminating potential donors. Accordingly, the Reproductive Council of the AATB has initiated steps to modify its standards to the age limit of 40.
Chromosome Aberrations↗
Paternal age and trisomy among spontaneous abortions.
The relationship of paternal age to specific types of trisomy and to chromosomally normal loss was investigated in data drawn from a case-control study of spontaneous abortions. Differences in paternal age between karyotype groups and controls delivering after 28 weeks gestation were tested using an urn model analysis which adjusted, by regression, for maternal age and, by stratification, for the effects of design variables (payment status, phase of study) and demographic factors (language, ethnicity). The magnitude of paternal age differences was estimated using least squares regression analysis. For chromosomally normal cases there was no association with paternal age. Among the fourteen trisomy categories examined, four (7, 9, 18, 21) showed increased paternal age (greater than or equal to 1 year above expectation), three (13, 20, 22) showed decreased paternal age and the rest, including the most common, trisomy 16, showed negligible differences. Only the association with trisomy 22 was statistically significant (P = 0.012), with a predicted reduction in paternal age of 2.1 years (95% CI -4.9, -0.5 years). This association did not vary with maternal age, payment status, phase of study, language or ethnicity. Because previous observations are extensive, the relation of paternal age to trisomy 21 was examined further. The overall association was not significant (beta = 0.8 years; 95% CI -0.8, 2.4 years). Moreover, there was evidence that the magnitude and direction of paternal age associations vary significantly within the sample, although not between subgroups defined on the basis of payment, phase of study, language or ethnicity. With respect to maternal age, the trend is towards a greater paternal age difference for trisomy 21 losses in younger women (P = 0.058). Given the number of tests performed, the finding for trisomy 22 and reduced paternal age could be due to chance. Among trisomy types, the direction of paternal age associations was not consistent for chromosomes grouped according to characteristics that might relate to the probability of nondisjunction, such as size, arm ratio, or nucleolar organizer region content, or to the potential viability of the trisomy. Thus, neither on statistical nor biological grounds do the data provide compelling evidence of paternal age effects on the trisomies found among spontaneous abortions, or on chromosomally normal losses.
Abortion, Spontaneous↗
Reexamination of paternal age effect in Down's syndrome.
Paternal age distribution for 1279 cases of Down's syndrome born in 1952--1968 was compared with the corresponding distribution for the general population, corrected for the maternal age as well as for the year of birth of the patients. Although there was no difference in the mean paternal age, the two distributions differed significantly, largely due to the excess of fathers aged 55 years and over and to the deficit of those aged 40--44 years in the patients born to mothers aged 30 years and over. The overall pattern of the relative incidence of Down's syndrome with advancing paternal age, with maternal age controlled, seems consistent with the hypothesis proposed by Stene et al. (1977). It increased from 0.8 for fathers aged 20--24 years slowly up to 1.2 for those aged 45--49 years, though with an intermediate drop to 0.8 at the age of 40--44 years, and then sharply to 2.4 for those aged 55 years and over. This rising pattern of the relative incidence with paternal age was essentially the same for the patients born in 1952--1960 and for those born in 1961--1968, although the slope was less steep in the latter than in the former group.
Adolescent↗
Extra structurally abnormal chromosomes (ESAC) detected at amniocentesis: frequency in approximately 75,000 prenatal cytogenetic diagnoses and associations with maternal and paternal age.
We analyzed rates of extra structurally abnormal chromosomes (ESAC) detected in prenatal cytogenetic diagnoses of amniotic fluid reported to the New York Chromosome Registry. These karyotypes include both extra unidentified structurally abnormal chromosomes (EUSAC)--often denoted as "markers"--and extra identified structurally abnormal chromosomes (EISAC). The rate of all EUSAC was 0.64/1,000 (0.32-0.40/1,000 mutant and 0.23-0.32 inherited), and that of all EISAC was 0.11/1,000 (0.07/1,000 mutant and 0.04/1,000 inherited). The rate of all ESAC was approximately 0.8/1,000-0.4-0.5/1,000 mutant and 0.3-0.4/1,000 inherited. Mean +/- SD maternal age of mutant cases was 37.5 +/- 2.9, significantly greater than the value of 35.8 years in controls. A regression analysis indicated a rate of change of the log of the rate of about +0.20 with each year of maternal age between 30 and 45 years. When paternal age was introduced, the maternal age coefficient increased to about +0.25--close to that seen for 47, +21--but the paternal age coefficient was -0.06. After being matched for maternal age and year of diagnosis, the case-control difference in paternal age for 24 mutant cases was -2.4 with a 95% confidence interval of -4.6 to -0.1 years. In a regression analysis of the effects of both parental ages on the (log) rate, the maternal age coefficient was +0.25 and the paternal age coefficient was -0.06. These results are consistent with a (weak) negative paternal age effect in the face of a strong maternal age effect. Since ESAC include a heterogeneous group of abnormalities, the maternal age and paternal age trends, if not the result of statistical fluctuation or undetected biases, may involve different types of events. Data in the literature suggest that chromosomes with de novo duplicated inversions of 15p have a strong maternal age effect (but little paternal age effect). Such chromosomes, however, do not account for the active maternal age trends seen in the data analyzed here. Inherited ESAC exhibited no such trends.
Adolescent↗
Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta.
The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congénitas series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 +/- 6.74 years in the IPIMC, and 37.19 +/- 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 +/- 7.08 years in the IPIMC, and 36.41 +/- 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 +/- 9.25 years, but not in the IPIMC, 32.26 +/- 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area.
Achondroplasia↗
An analysis for paternal-age effect in Ohio's Down syndrome births, 1970-1980.
The purpose of this study was to analyze Down syndrome (DS) births during 1970-1980 in the State of Ohio for a paternal-age effect independent of maternal age. Birth certificates and chromosome analysis records were used to ascertain 1,244 white DS births, which by capture-recapture methodology were estimated to comprise two-thirds of all white DS births in Ohio for this period. The control data consisted of 1,667,210 white live births in Ohio during the same period. One method of statistical analysis was a case-control comparison, which for each single-year maternal age compares the mean paternal age for controls with each observed DS paternal age. No statistically significant paternal-age effect was found in nine of the 11 years. For two of the years, and for all years combined, the DS fathers were significantly younger than the fathers of controls. When the data were subdivided according to ascertainment, one subpopulation--those DS individuals obtained from birth certificates alone--also showed a statistically significant negative paternal-age effect. The Mantel-Haenszel test was also applied to these data. Assuming no paternal-age effect, a lower rate of DS births than expected was found at paternal ages greater than or equal to 40, but not at greater than or equal to 45, greater than or equal to 50, or greater than or equal to 55. These same methods were used to test for a maternal-age effect. In each of the 11 years and over all 11 years combined, a strong and statistically significant positive maternal-age effect was detected.
Adolescent↗
Paternal age and the risk of congenital heart defects.
The effect of paternal age on the risk of birth defects among offspring is less well studied than the effect of maternal age, with few comprehensive epidemiologic studies having been conducted. Advanced paternal age has been shown to be associated with an increase in new dominant mutations that result in particular congenital anomalies. The relationship between paternal age and more common birth defects, for example, cardiac defects, has not been as extensively evaluated. Therefore, a total of 4,110 cases of congenital heart defects was identified from the British Columbia Health Surveillance Registry. Matched controls were obtained from the birth files of British Columbia for the years 1952-1973. Prevalence odds ratios for paternal age, adjusted for maternal age and other factors, were estimated for 8 cardiac defect groups. A suggestive general pattern of increasing risk with increasing age among cases (excluding chromosomal anomalies) relative to controls was found for ventricular septal defects (VSD), atrial septal defects (ASD), and patent ductus arteriosus (PDA). In addition, an increased risk among men younger than 20 yr was found for VSD and ASD. These findings are consistent with the results of some previous epidemiologic studies. Based on the results of this study it is estimated that for cardiac defects such as VSD, approximately 5% of cases may be due to advanced paternal age (> 35 yr), possibly through dominant mutations.
Adult↗
Paternal age and the occurrence of birth defects.
The association between paternal age and the occurrence of birth defects was studied using data collected in Metropolitan Atlanta. Paternal-age information for babies born with defects was obtained from birth certificates, hospital records, and interviews with mothers; for babies born without defects, the information was obtained from birth certificates. Several statistical techniques were used to evaluate the paternal-age-birth-defects associations for 86 groups of defects. Logistic regression analysis that controlled for maternal age and race indicated that older fathers had a somewhat higher risk for having babies with defects, when all types of defects were combined; an equivalent association for older mothers was not found. Logistic regression analyses also indicated modestly higher risks for older fathers for having babies with ventricular septal defects and atrial septal defects and substantially higher risks for having babies with defects classified in the category chondrodystrophy (largely sporadic achondroplasia) and babies with situs inversus. An association between elevated paternal age and situs inversus has not been reported before; the magnitude of the estimated increased risk for situs inversus was about the same as that found in this study for chondrodystrophy.
Congenital Abnormalities↗
Paternal age and Down's syndrome diagnosed prenatally: no association in French data.
An investigation of a paternal age effect independent of maternal age was undertaken for 118 trisomy 21 cases diagnosed prenatally in 6656 amniocenteses. The mean of the difference delta in paternal age of Down's syndrome cases compared to those with normal genotypes after controlling for maternal age was +0.46 with a 95 per cent confidence interval of -0.84 to +1.76. This revealed no evidence for a paternal age effect. Multiple applications of the Mantel-Haenszel test revealed no statistically significant evidence for a paternal age effect independent of maternal age. These results are in agreement with those of Hook and Cross (1982b) but not with claims of Stene et al. (1981), of a strong paternal age effect detected in studies on prenatal diagnosis. The hypothesis suggested by Hook and Cross (1982a) that there is a rather weak paternal age effect independent of maternal age in most if not all populations cannot be excluded. If temporal or geographic factors account for the differences in studies on paternal age effect, extrapolation to other time periods or populations cannot be done.
Adolescent↗
On the inadequacy of quinquennial data for analyzing the paternal age effect on Down's syndrome rates.
Investigations of the influence of paternal age on the rate of Down's syndrome are complicated by the high correlation between parental ages and the strong dependence of the incidence rate upon maternal age. Two possible approaches to isolating an independent paternal age effect are shown to lead to erroneous results if based on data by quinquennial age intervals rather than by single-year intervals. For a multiple regression method the discrepancy can be removed by using the mean maternal and mean paternal age within each quinquennial cell. Failure to do so results in an artifactual paternal age effect.
Down Syndrome↗
Down syndrome, paternal age, maternal age and birth order.
Recent cytogenetic evidence has shown that trisomy 21 can arise, perphaps even in substantial proportion, from paternal nondisjunction. The statistical association between Down syndrome incidence and maternal age, paternal age and birth order has been studied in a sample of over 4000 cases. The size of this sample made it possible to control for the effect of maternal age by single years of age during the search for a paternal age effect and vice versa, and the importance of such stringent control is emphasized. The maternal age association was confirmed with an extremely high degree of statistical significance while no independent effect of paternal age was found; indeed, the rates at paternal ages over 45 years appear to be nearly constant. After adjusting for the effects of parental age, a significant inverse association of birth order with incidence was noted. It also appears that the incidence among very young mothers may be high: for maternal ages 15 years and less the rates seem to be equivalent to those found at 30 or 35 years. In order to help answer the question of whether the maternal age association is the result of increasing rates of nondisjunction or of some other mechanism (for example, an age related defect in a spontaneous abortion screening mechanism), the proportion of cases due to maternal and paternal nondisjunction at different parental ages must be determined.
Adolescent↗
A search for a paternal-age effect upon cases of 47, +21 in which the extra chromosome is of paternal origin.
If there is a paternal-age effect for 47, +21, it would appear most likely to be present primarily, if not exclusively, in cases in which the extra chromosome is of paternal origin. To search for such an effect, data were reviewed from seven series reporting at least four cases of 47, +21 of paternal origin. The mean of the paternal age-maternal-age difference of such cases (dp) in each series was compared with the mean of the paternal-age differences of cases in the same series that were of maternal origin (dm). If the difference between these (dp - dm or delta) is greater than zero, then this would imply a positive paternal-age effect among cases of paternal origin, at least compared to those of maternal origin. In the seven series, the values of delta ranged from -2.2 years to +3.4 years, and there was no evidence in these comparisons for any consistent trend. A second analysis controlled for any effect of maternal-age variation upon this difference. Each case of paternal origin was matched with a case of maternal origin in the same series that was of the same maternal age. Of 60 cases of paternal origin, exact matches were found for 38. In these 38, the mean value of the difference in parental ages, dp - dm or delta, was negative, about -1.1 (+/- 5.1 years). The difference was highest for the nine cases of paternal origin in which the extra chromosome resulted from presumptive second-division non-disjunction, -1.8 (+/- 3.8 years).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Reexamination of paternal age effect in Down's syndrome.
The recent discovery that the extra chromosome in about 30% of cases of 47, trisomy 21 is of paternal origin has revived interest in the possibility of paternal age as a risk factor for a Down syndrome birth, independent of maternal age. Parental age distribution for 611 Down's syndrome 47, +21 cases was studied. The mean paternal age was 0.16 year greater than in the entire population of live births after controlling for maternal age. There was no evidence for a significant paternal age effect at the 0.05 level. For 242 of these Down's syndrome cases, control subjects were selected by rigidly matching in a systematic manner. Paternal age was the variable studied, with maternal age and time and place of birth controlled. There was no statistically significant association between paternal age and Down's syndrome. After adjustment for maternal age, these two studies were not consistent with an increase of paternal age in Down's syndrome.
Adolescent↗
Genetic counseling dilemmas: Down syndrome, paternal age, and recurrence risk after remarriage.
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Down Syndrome↗
On methodological issues regarding 47,+21 paternal age data.
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Adolescent↗